Selective Inhibition of Tumor Growth by Clonal NK Cells Expressing an ErbB2/HER2-Specific Chimeric Antigen Receptor

• DOI: 10.1038/mt.2014.219
• Publication Date: 2014-11-06T12:16:31Z
• Authors: Kurt Schönfeld; Christiane Sahm; Congcong Zhang; Sonja Naundorf; Christian Brendel; Marcus Odendahl; Paulina Nowakowska; Halvard Bönig; Ulrike Köhl; Stephan Kloess; Sylvia Köhler; Heidi Holtgreve-Grez; Anna Jauch; Manfred Schmidt; Ralf Schubert; Klaus Kühlcke; Erhard Seifried; Hans G Klingemann; Michael A Rieger; Torsten Tonn; Manuel Grez; Winfried S Wels
• Keywords: Cytotoxicity, Immunologic; 0301 basic medicine; Receptor, ErbB-2; Genetic Vectors; Epitopes, T-Lymphocyte; Gene Expression; Breast Neoplasms; Immunophenotyping; Clonal Evolution; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Drug Discovery; Genetics; Animals; Humans; Molecular Biology; Cell Line, Transformed; Pharmacology; Lentivirus; 3. Good health; Killer Cells, Natural; Disease Models, Animal; Phenotype; Molecular Medicine; Female; Immunotherapy; Lymphocyte Culture Test, Mixed

Natural killer (NK) cells are an important effector cell type for adoptive cancer immunotherapy. Similar to T cells, NK cells can be modified to express chimeric antigen receptors (CARs) to enhance antitumor activity, but experience with CAR-engineered NK cells and their clinical development is still limited. Here, we redirected continuously expanding and clinically usable established human NK-92 cells to the tumor-associated ErbB2 (HER2) antigen. Following GMP-compliant procedures, we generated a stable clonal cell line expressing a humanized CAR based on ErbB2-specific antibody FRP5 harboring CD28 and CD3ζ signaling domains (CAR 5.28.z). These NK-92/5.28.z cells efficiently lysed ErbB2-expressing tumor cells in vitro and exhibited serial target cell killing. Specific recognition of tumor cells and antitumor activity were retained in vivo, resulting in selective enrichment of NK-92/5.28.z cells in orthotopic breast carcinoma xenografts, and reduction of pulmonary metastasis in a renal cell carcinoma model, respectively. γ-irradiation as a potential safety measure for clinical application prevented NK cell replication, while antitumor activity was preserved. Our data demonstrate that it is feasible to engineer CAR-expressing NK cells as a clonal, molecularly and functionally well-defined and continuously expandable cell therapeutic agent, and suggest NK-92/5.28.z cells as a promising candidate for use in adoptive cancer immunotherapy.